Although the role of abnormal bronchial secretions in the pathogenesis of airway obstruction is recognized by clinicians and pathologists, this aspect of bronchial asthma has been insufficiently examined in the past. During the current grant period, a series of experiments have been conducted in our laboratory in an attempt to characterize mucociliary function in a sheep model of allergic bronchoconstriction. These studies have demonstrated that 1) antigen-induced bronchospasm in allergic conscious sheep sensitized with Ascaris suum shares important physiologic features with human bronchial asthma, 2) antigen-induced bronchospasm is associated with an impairment of mucociliary transport and ciliary activity, 3) in vitro exposure of tracheal tissue from sensitized animals to antigen stimulates mucous secretion. The first objective of the present proposal is to further investigate the mechanism of mucociliary dysfunction in allergic asthma and to determine the role of chemical mediators of anaphylaxis. The mediator effects will be assessed by pretreatment with selective blocking agents prior to antigen challenge in vivo, and the use of selective agonists in vitro. Mucous velocity and rheology will be measured with a radiographic and capillary technique, respectively, and ciliary function with a microscopic technique using tracheal brush preparations. An Ussing chamber will be used to measure in vitro mucus secretion, and ion transport. The second objective is to determine if decreased transport and increased amounts of airway mucus impair host defenses. One set of experiments will attempt to demonstrate the potentially toxic effect of airway mucus on macrophages, while the possible facilitation of pulmonary infection will be studied with an experimental pneumonia model. We expect that the information derived from these studies will contribute to the understanding of the mechanisms controlling the secretion and transport of airway mucus in allergic asthma and to demonstrate some of the detrimental consequences of asthma-associated mucociliary dysfunction. The obtained results could form the basis for pharmacological intervention.